Soy is known to lower cholesterol levels and this corresponds to a decrease in cardiovascular disease risk. However, the mechanisms of this hypocholesterolemic effect as well as the components of soy that cause this effect are a source of controversy. It is also unknown whether soy protein containing endogenous isoflavones would have the same effect as soy protein containing low isoflavones with isoflavones supplemented back to the protein source. We have previously shown in a cell culture model that the isoflavones, genistein and daidzein, increase the processing of the Sterol Regulatory Element Binding Proteins (SREBPs) and the expression SREBP-regulated genes such as HMG CoA reductase, HMG CoA synthase and the LDL receptor. This study will address whether isoflavones cause a similar increase in SREBP processing and SREBP-regulated gene expression in an in vivo model. We will use the C57BL/6J mouse and feed it an atherogenic diet for either 2 days, 10 days or 6 weeks. The diets will contain soy protein with low endogenous amounts of isoflavones with or without isoflavone supplementation or soy protein with high amounts of endogenous isoflavones. The animals will be sacrificed and their plasma and liver tissue lipids will be analyzed. The processing of SREBP-2 and the protein levels of HMG CoA reductase will be measured by immunoblotting. The expression levels of SREBP-regulated genes will also be investigated by quantitative real time PCR. We hypothesize that there will be a decrease in plasma cholesterol and triglyceride levels and this will correspond to an increase in SREBP processing as well as SREBP-regulated gene expression. However, we do not know if we will observe the same results for soy protein containing high amounts of endogenous isoflavones or soy protein containing low amounts of isoflavones with isoflavones supplemented back to the protein source. PUBLIC HEALTH RELEVANCE: Cardiovascular disease and hypercholesterolemia are one of the major causes of death in the United States. This project seeks to investigate the mechanisms by which an inexpensive dietary component, soy isoflavones, lowers cholesterol levels.